The invention relates to a bioerodible polymeric composition, a method of making such a composition, and a controlled delivery device comprising the composition.
Bioerodible polymeric compositions are well-known materials useful for administering pharmaceutical medicaments. One advantage of a drug delivery system prepared from a bioerodible polymer is that the polymer erodes in an aqueous environment. As the polymer erodes, the drug is released from the polymeric matrix. The erosion of the polymer in the aqueous physiological environment of a mammal during the concomitant release of the drug obviates the need to remove the delivery system once the medicament is expended.
The rate of drug release from the matrix has been determined to have a direct relationship with the rate of degradation of the polymeric material. Traditionally, it has been understood that the drug release from the matrix is triggered by the hydrolysis of the polymer. The drug concomitantly diffuses away from the polymeric matrix as the polymeric chains of the matrix hydrolyze. For this reason, efforts related to modifying the drug release from and the degradation rate of the polymeric composition have focused on protecting the polymer against hydrolysis.
It is widely accepted that changes in the structure of the polymeric backbone are necessary to modify the hydrophobicity properties of the polymer. Mark et al., Encyclopedia of Polymer Science and Engineering, Vol. 22, John Wiley and Sons, 1985. Accordingly, attempts to improve the release profile of polymeric matrices have been directed toward altering the molecular weight of the polymeric backbone.
U.S. Pat. No. 4,857,311, for example, describes polyanhydrides with a uniform distribution of aliphatic and aromatic residues. The uniform distribution of aliphatic and aromatic residues in the chain allows for uniform degradation at a rate useful for controlled bioactive delivery.
U.S. Pat. No. 4,888,176 describes the preparation of high molecular weight polyanhydride controlled delivery devices.
U.S. Pat. No. 4,789,724 describes the preparation of very pure anhydride co-polymers of aromatic and aliphatic diacids.
U.S. Pat. No. 5,010,167 describes a biodegradable poly(amide- and imide-co-anhydride) prepared by the co-polymerization of amido- or imido-dicarboxylic acid monomers with other dicarboxylic acids.
U.S. Pat. No. 5,171,812 describes a polyanhydride synthesized from monomers prepared by linking two or more unsaturated aliphatic carboxylic acids.
However, the rate of release at any given temperature is crucially dependent on the molecular weight of the polymeric constituents of the drug delivery matrix. Even under strictly anhydrous conditions, the bioerodible polymer undergoes a decrease in the average molecular weight. This phenomenon is inconsistent with a hydrolytic degradation mechanism.
Abraham Domb and Robert Langer have proposed that the anhydrous degradation of a polymeric matrix is a consequence of self-depolymerization of the polymeric backbone via inter- and intramolecular interchange. Macromolecules, 22, 2117-2122 (1989). For example, in its lowest Gibbs free energy geometry, the inter- and intrachain alignment of the carbonyl groups of a polyanhydride matrix allows for nucleophilic attack of the anhydride oxygen on the carbonyl carbon of the adjacent polymeric chain. The self-depolymerization mechanism leads to the gradual loss of the average molecular weight of the polymer. The decrease of the molecular weight of the polymer directly affects the rate at which the drug in the matrix diffuses away from the polymeric matrix. The self-depolymerization mechanism is believed to occur independently of the hydrolytic degradation mechanism.
The recognition of a self-depolymerizing mechanism in the bioerodible matrices provides new possibilities for modifying the degradation rate in a polymeric matrix. In particular, one or more pharmaceutically acceptable additives can be blended with the polymer to provide a new polymeric material having either an increased or a decreased rate of degradation relative to the degradation rate of the polymeric starting material.
There is no precedent of modifying the rate of degradation in a bioerodible polymeric composition by blending the polymer with additive. In one instance, U.S. Pat. No. 5,122,367 describes a controlled release implant claiming that sugar is a stabilizing agent for the release of an active growth hormone from the implant. However, the sugar is co-lyophilized with the growth hormone to affect release of the hormone. The co-lyophilization of the sugar with the growth hormone stabilizes the hormone. There is no description of the sugar having any effect on the degradation of the polymeric matrix.
Therefore, there remains a need for providing a bioerodible polymeric matrix having a reproducible drug release rate. It would be beneficial to have a polymeric matrix in which the degradation rate of the matrix can be increased or decreased in a reproducible manner when compared with the degradation rate of the starting polymer.
The invention relates to a bioerodible polymeric composition and a method for preparing the same. The bioerodible polymer comprises covalently bonded repeating units, commonly referred to as monomers. The polymer is blended with a pharmaceutically acceptable additive to afford a polymer having modified degradation characteristics. The resulting composition possesses the characteristics of hydrophobicity, stability, strength, flexibility, organic solvent solubility, low melting point and an appropriate degradation profile suitable for being incorporated into a controlled delivery device.
One embodiment of the composition comprises the bioerodible polymer and an accelerant additive. The accelerant additive is a compound having a hydrophilic and a hydrophobic domain, such as in a detergent. In this embodiment, the hydrophilic and the hydrophobic domains of the additive associate with the respective hydrophilic and the hydrophobic domains of the polymer. The resulting composition exhibits an increased rate of polymer degradation. The increased rate of degradation in the polymer can be beneficial for preparing a delivery device for medicament having a more rapid rate of controlled release when compared with a device prepared from the same polymer, but without additives.
Another embodiment of the composition comprises the bioerodible polymer and a retardant additive. The retardant additive is a compound that is chemically non-reactive in the polymeric matrix environment. The chemically non-reactive additive shields the inter- and intramolecular nucleophilic attack of the functional groups in the polymeric chain. The presence of the additive retards the rate of degradation in the polymer, allowing for the effect of delayed release of the medicament.
The method of the invention comprises blending a bioerodible polymer with a pharmaceutically acceptable additive. The method provides a new bioerodible polymer having modified degradation characteristics. The method can be used to prepare bioerodible polymeric compositions having a repeatable rate of degradation that is either increased or decreased when compared to the starting polymer.
The steps for preparing the polymeric composition comprise:
(a) melting the bioerodible polymer at a temperature above the glass transition temperature of the polymer; and
(b) adding and blending a pharmaceutically acceptable additive to the polymer.
The polymer blend can be extruded, melted and mixed to provide the desired polymeric matrix. The blend can also be molded under adequate temperature and pressure conditions, for example by injection or compression molding techniques, to provide a polymeric composition of the desired shape.
The composition can be modified to provide a controlled delivery device for a pharmaceutical medicament. The controlled delivery device will be suitable for administering practically any medicament. The controlled delivery device will exhibit a reproducible, modified rate of degradation when compared to the degradation rate of the starting polymer.